Rheumatoid arthritis (RA) is a chronic auto-immune disease, which causes inflammation of the joints that eventually leads to progressive joint destruction and deformity. Patients have swollen, stiff and painful joints. The main aim of treatment is to reduce swelling and inflammation, to alleviate pain and stiffness and to maintain normal joint function. While there is no cure, it is important to properly manage pain.

The mainstays of therapy in RA are disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs). These drugs primarily target inflammation. However, since inflammation is not the only factor that causes pain in RA, patients may not be (fully) responsive to treatment with these medications.
Opioids are another class of pain-relieving substance (analgesics). They are frequently used in RA, but their role in chronic cancer pain, including RA, is not firmly established.

A recent Cochrane Systematic Review [1] assessed the beneficial and harmful effects of opioids in RA.

Eleven studies (672 participants) were included in the review.

Four studies only assessed the efficacy of single doses of different analgesics, often given on consecutive days. In each study opioids reduced pain (a bit) more than placebo. There were no differences in effectiveness between the opioids.

Seven studies between 1-6 weeks in duration assessed 6 different oral opioids either alone or combined with non-opioid analgesics.
The only strong opioid investigated was controlled-release morphine sulphate, in a single study with 20 participants.
Six studies compared an opioid (often combined with an non-opioid analgesic) to placebo. Opioids were slightly better than placebo in improving patient reported global impression of clinical change (PGIC) (3 studies, 324 participants: relative risk (RR) 1.44, 95% CI 1.03 to 2.03), but did not lower the number of withdrawals due to inadequate analgesia in 4 studies.
Notably none of the 11 studies reported the primary and probably more clinical relevant outcome “proportion of participants reporting ≥ 30% pain relief”.

Comparing opioids to other analgesics instead of placebos seems more relevant. Among the 11 studies, only 1 study compared an opioid (codeine with paracetamol) to an NSAID (diclofenac). This study found no difference in efficacy or safety between the two treatments.

The 11 included studies were very heterogeneous (i.e. different opioid studied, with or without concurrent use of non-opioid analgesics, different outcomes measured) and the risk of bias was generally high. Furthermore, most studies were published before 2000 (less optimal treatment of RA).

The authors therefore conclude:

In light of this, the quantitative findings of this review must be interpreted with great caution. At best, there is weak evidence in favour of the efficacy of opioids for the treatment of pain in patients with RA but, as no study was longer than six weeks in duration, no reliable conclusions can be drawn regarding the efficacy or safety of opioids in the longer term.

This was the evidence, now the opinion.

I found this Cochrane Review via an EvidenceUpdates email alert from the BMJ Group and McMaster PLUS.

EvidenceUpdate alerts are meant to “provide you with access to current best evidence from research, tailored to your own health care interests, to support evidence-based clinical decisions. (…) All citations are pre-rated for quality by research staff, then rated for clinical relevance and interest by at least 3 members of a worldwide panel of practicing physicians”

I usually don’t care about the rating, because it is mostly 5-6 on a scale of 7. This was also true for the current SR.

There is a more detailed rating available (when clicking the link, free registration required). Usually, the newsworthiness of SR’s scores relatively low. (because it summarizes ‘old’ studies?). Personally I would think that the relevance and newsworthiness would be higher for the special interest group, pain.

But the comment of the first of the 3 clinical raters was most revealing:

He/she comments:

As a Palliative care physician and general internist, I have had excellent results using low potency opiates for RA and OA pain. The palliative care literature is significantly more supportive of this approach vs. the Cochrane review.

Thus personal experience wins from evidence?* How did this palliative care physician assess effectiveness? Just give a single dose of an opiate? How did he rate the effectiveness of the opioids? Did he/she compare it to placebo or NSAID (did he compare it at all?), did he/she measure adverse effects?

And what is “The palliative care literature” the commenter is referring to? Apparently not this Cochrane Review. Apparently not the 11 controlled trials included in the Cochrane review. Apparently not the several other Cochrane reviews on use of opioids for non-chronic cancer pain, and not the guidelines, syntheses and synopsis I found via the TRIP-database. All conclude that using opioids to treat non-cancer chronic pain is supported by very limited evidence, that adverse effects are common and that long-term use may lead to opioid addiction.

I’m sorry to note that although the alerting service is great as an alert, such personal ratings are not very helpful for interpreting and *true* rating of the evidence.

I would rather prefer a truly objective, structured critical appraisal like this one on a similar topic by DARE (“Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects”) and/or an objective piece that puts the new data into clinical perspective.

*Just to be clear, the own expertise and opinions of experts are also important in decision making. Rightly, Sackett [2] emphasized that good doctors use both individual clinical expertise and the best available external evidence. However, that doesn’t mean that one personal opinion and/or preference replaces all the existing evidence.

This week I was attending another congress, the Continental European Cochrane Entities Meeting(CECEM).

This annual meeting is meant for staff from Cochrane Entities, thus Centre Staff, RGC’s (Review Group Coordinators), TSC’s (Trial Search Coordinators) and other staff members of the Cochrane Collaboration based in Continental Europe.

CECEM 2009 was held in Maastricht, the beautiful old Roman city in the South of the Netherlands. The city where my father was born and where I spend many holidays.

One interesting presentation was by Cochranes’ 1st Editor in chief, David Tovey, previouslyGP in an urban practice in London for 14 years and Editorial Director of the BMJ Group’s ‘Knowledge’ division (responsible for BMJ Clinical Evidence and its sister product Best Treatments, see announcement in Medical News Today)

David began with saying that the end user is really the key person and that the impact of the Cochrane Reviews is most important.

“How is it that a Senior health manager in the UK may shrug his shoulders when you ask him if he has ever heard of Cochrane?”

“How do we make sure that our work had impact? Should we make use of user generated content?”

Quality is central, but quality depends on four pillars. Cochrane reviews should be reliable, timely, relevant and accessible.

How quality is perceived is dependent on the end users. There are several kinds of end users, each with his own priorities.

doctor: wants comprehensive and up-to-date info, wants to understand and get answers quickly.

patient: trustworthiness, up-to-date, wants to be able to make sense of it.

scientist: wants to see how the conclusions are derived.

policy and guideline-makers.

Reliable: Several articles have shown Cochrane Systematic Reviews to be more reliable then other systematic reviews (Moher, PLOS BMJ)*

Timely: First it takes time to submit a title of a Cochrane Review and then it takes at least 2 years before a protocol becomes a review. Some reviews take even longer than 2 years. So there is room for improvement.

Patients are also very important as end user. Strikingly, the systematic review about the use of cranberry to prevent recurrent urinary tract infection is the most frequently viewed article,- and this is not because the doctors are most interested in this particular treatment….

Doctors: Doctors often rely on their colleagues for a quick and trustworthy answer. Challenge: “can we make consulting the Cochrane Library as easy as asking a colleague: thus timely and easy?”

make clear what an update means and how important this update is: are there new studies found? are these likely to change conclusions or not? When was the last amendment to the search?

I found the presentation very interesting. What I also liked is that David stayed with us for two days -also during the social program- and was easy approachable. I support the idea of a user-centric approach very much. However, I had expected the emphasis to be less on the timeliness (of updates for instance), but more on how users (patients, doctors) can get more involved and how we review the subjects that are most urgently needed. Indeed, when I twittered that Tovey suggested that we “make consulting the Cochrane Library as easy as asking a colleague”, Jon Brassey of TRIP answered that a lot has to be done to fulfill this, as the Cochrane only answers 2 out of 350+ questions asked by GPs in the UK, a statement that appeared to be based on his own experience (Jon is founder of the TRIP-database).

But in principle I think that Jon is correct. Right now too few questions (in the field of interventions) are directly answered by Cochrane Systematic Reviews and too little is done to reach and involve the Cochrane Library users.

click to enlarge

During the CECEM other speakers addressed some of these issues in more detail. André Knottnerus, Chair of the Dutch Health Council, discussed “the impact of Cochrane Reviews”, and Rob the Bie of the Rehabilitation & Related Therapies field discussed “Bridging the gap between evidenced based practice and practice based evidence”, while Dave Brooker launched ideas about how to implement Web 2.0 tools. I hope to summarize these (and other) presentations in a blogpost later on.

*have to look this up

NOTE (2009-11-10).

I had forgotten about this blank “citation” till this post was cited quite in another context (see comment: http://e-patients.net/archives/2009/11/tell-the-fda-the-whole-story-please.html) and someone commented that the asterisk to the “the amazing statement” had still to be looked up, indirectly arguing that this statement thus was not reliable- and continuing by giving an example of a typically flawed Cochrane Review that hit the headlines 4 years ago, a typical exception to the rule that “Cochrane systematic reviews are more reliable than other systematic reviews”. Of course when it is said that A is more trustworthy than B it is meant on average. I’m a searcher, and on average the Cochrane searchers are excellent, but when I do my best I surely can find some that are not good at all. Without doubt that also pertains to other parts of Cochrane Systematic Reviews.
In addition -and that was the topic of the presentation- there is room for improvement.

Now about the asterisk, which according to Susannah should have been (YIKES!) 100 times bigger. This was a post based on a live presentation and I couldn’t pick up all the references on the slides while making notes. I had hoped that David Tovey would have made his ppt public, so I could have checked the references he gave. But he didn’t and so I forgot about it. Now I’ve looked some references up, and, although they might not be identical to the references that David mentioned, they are in line with what he said:

The PLoS Medicine Editors 2007 Many Reviews Are Systematic but Some Are More Transparent and Completely Reported than Others. PLoS Med 4(3): e147. doi:10.1371/journal.pmed.0040147 (free full text; editorial coment on [1]

As an information specialist I will concentrate on Chapter 6: Searching for studies.

This chapter consist of the following paragraphs:

6.1 Introduction

6.2 Sources to search

6.3 Planning the search process

6.4 Designing search strategies

6.5 Managing references

6.6 Documenting and reporting the search process

6.7 Chapter information

6.8 References

As the previous versions the essence of the Cochrane searches is to perform a comprehensive (sensitive) search for relevant studies (RCTs) to minimize bias. The most prominent changes are:

1. More emphasis on the central role of the Trial Search Coordinator (TSC) in the search process.
Practically each paragraph summary begins with an advice to consult the TSC, i.e. in 6.1: Cochrane review authors should seek advice from the Trials Search Co-ordinator of their Cochrane Review Group (CRG) before starting a search.

One of the main roles of TSC’s is the assisting of authors with searching, although the range of assistance may vary from advise on to how run searches to designing, running and sending the searches to authors.

I know from experience that most authors have not enough search literacy to be able to satisfactory complete the entire search on their own. Not even all librarians may be equipped to perform such exhaustive searches. That is why the handbook says: “If a CRG is currently without a Trials Search Co-ordinator authors should seek the guidance of a local healthcare librarian or information specialist, where possible one with experience of conducting searches for systematic reviews.”

Another essential core function of the TSC is the development and maintenance of the Specialized Register, containing all relevant studies in their area of interest, and submit this to CENTRAL (The Cochrane Central Register of Controlled Trials) on a quarterly basis”. CENTRAL is the most comprehensive source of reports of controlled trials (~500,000 records), available in “The Cochrane Library” (there it is called CLINICAL TRIALS). CENTRAL is available to all Cochrane Library subscribers, whereas the Specialized Register is only available via the TSC.

Redrawn from the Handbook Fig. 6.3.a: The contents of CENTRAL

2. Therefore Trials registers are an increasingly important source of information. CENTRAL is considered to be the best single source of reports of trials that might be eligible for inclusion in Cochrane reviews. However, other than would be expected (at least by many authors) a search of MEDLINE (PubMed) alone is not considered adequate.

The approach now is: Specialized Registers/CENTRAL and MEDLINE should be searched as a minimum, together with EMBASE if it is available (apart from topic specific databases, snowballing). MEDLINE should be searched from 2005 onwards, since CENTRAL contains all records from MEDLINE indexed with the Publication Type term ‘Randomized Controlled Trial’ or ‘Controlled Clinical Trial’ (a substantial proportion of theses MEDLINE records have been retagged as a result of the work of The Cochrane Collaboration (Dickersin 2002)).

Personally, for non-Cochrane searches, I would rather search the other way around, MEDLINE (OVID) first, than EMBASE (OVID) and finally CENTRAL, and deduplicate the searches afterwards (in Reference Manager for instance). The (Wiley) Cochrane Library is not easy to search (for non-experienced users, i.e. you have to know the MESH beforehand, there is (yet) no mapping). If you start your search in MEDLINE (OVID) you can easily transform it in EMBASE and subsequently CENTRAL (using both MESH and EMBASE keywords as well as textwords)

3. The full search strategies for each database searched need to be included in an Appendix with the total number of hits retrieved by the electronic searches included in the Results section. Indeed the reporting has been very variable, some authors only referring to the general search strategy of the group. This made the searching part less transparent.

4. Two new Cochrane Highly Sensitive Search Strategies for identifying randomized trials in MEDLINE strategies have been developed: a sensitivity-maximizing version and a sensitivity- and precision-maximizing version. These filters (that are to be combined with the subject search) were designed for MEDLINE-indexed records. Therefore, a separate search is needed to find non-indexed records as well. An EMBASE RCT filter is still under development.

These methodological filters will be exhaustively discussed in another post.

Regular breast exam, either by women theirselves (BSE, breast self exam) or a doctor or nurse, has been promoted for many years, because this would help to detect breast cancer earlier, and “when breast cancer is found earlier, it’s easier to treat and cure” . At least that is what most people believe and what has been advocated by organizations and Internet companies (i.e. selling special gloves) (see figure).

1. What is the conclusion from the study?The authors conclude that regular breast examination (BE) does more harm than good and is therefore not recommended.

2. Which harm, which good?Breast examination didn’t lower mortality (not beneficial), whereas it led to more unnecessary biopsies (harm).

3. Why did they look at mortality only?They didn’t, they also scored the number and stage of cancers identified. However mortality (or really survival) is an outcome that matters most for patients. Suppose the screening finds more breast cancers, but early intervention does not lead to any cure, than the early recognition of the cancer is of no real value to the patient.

4. Why are more unnecessary biopsies considered as harm?
Biopsies are an invasive procedure and lead to unnecessary anxiety, that can have a long-lasting effect on psychological well-being. Extra tests to rule out that it is not cancer also cost a lot of money. Whether it is ‘worth it’ depends on whether -and to which extent- people’s lives are saved (or quality of life improved).

5. What kind of study is it?It is a systematic review (of controlled clinical trials) made by the Cochrane Collaboration (see glossary). Generally these systematic reviews are of high methodological quality, because of the systematic and explicit methods used to identify, select and critically appraise relevant research. After extensively searching for all trials, only controlled clinical trials (studies of the highest evidence) with predefined characteristics are included. Thus authors are really looking for all the high level evidence there is, instead of grabbing some papers from the drawer or looking at the core English language journals only.

6. Is this new information? No, not really. In fact this systematic review is an update of a previous version, published in 2003. The studies included and the conclusions remain the same. As shown from the scheme below (taken from a figure in a very interesting opinion paper entitled “Challenges to cancer control by screening” (see abstract here), the attitude towards breast self examination already changed soon after the original trials were published.

M.N. Pollak and W.D. Foulkes: Nature Reviews Cancer 3, 297 (2003)

7. Omg? ….All Cochrane Systematic have to be regularly updated to see if there isn’t any new evidence that could alter the conclusions. In this case, after updating the search, no new studies of good quality were found. However, there are still some trials ongoing.

8. Can we rely on these conclusions? Is the Cochrane Review of good enough quality?The Cochrane Review itself is of high quality, but the two randomized studies included, one from Russia (1999: ~122,500 participants) and one from Shanghai (2002: ~266,000 participants) have some serious flaws. For instance, both studies did not have an adequate allocation concealment (keeping clinicians and participants unaware of the assignments). An inadequate concealment undermines the validity of a trial (see for instance this 2002 Lancet paper). Also, description of statistical methods was lacking. Furthermore, data from the Moscow-branch of the Russian study were incomplete (these are excluded), mammography might have been used additionally and in the Shanghai trial there was a large difference in all-cause mortality in favor of the control group, suggesting that the two groups were imbalanced from the start.

9. Can the results of these rather old trials from countries as China and Russia be directly translated to the situation in Western Countries with a high standard of care?Intuitively I would say ‘probably not’. However, we still don’t know whether the current western quality of care would actually lead to a better outcome after early detection, because it has never be tested in a well performed controlled trial.

10. Is this outcome applicable to anyone?No, the studies are applicable to healthy, middle-aged woman without any particular risk. Screening methods might be more useful or even required for woman at high risk (i.e. familiar predisposition, previous ovarian or breast cancer).

11. Still, in recent interviews experts in the field say they do know that BSE is beneficial. One doctor for instance referred (in this Medscape paper) to a recent trial, that concluded that breast self-examination should be promoted for early detection of breast cancer (see here).Either these doctors/experts give their personal opinion, refer to unpublished data or to studies with a lower evidence level. For instance the study referred to by Dr. Goldstein above was a retrospective study looking at how accurately woman could detect a breast tumor. Retrospective studies are more biased (see previous post on levels of evidence for dummies). Furthermore this study didn’t evaluate a hard outcome (survival, better prognosis) and there are just as many retrospective studies that claim the opposite, i.e. this article of Newcomb et al in J Natl Cancer Inst. 1991(abstract).

12. Should woman refrain from breast self examination then?I found a short article (half A4) in the Dutch woman’s magazine (!) Viva very clear and concise.
Four woman gave their opinion.
A patient who had had a previous breast tumor kept on checking it (high risk group).

The director of a patient association said: “there is no evidence that BSE is beneficial: don’t feel quilty if you don’t check your breasts. But it might have a reassuring effect if you do”.
The spokeswoman of the Dutch association “struggle against cancer” (KWF) said that they didn’t promote structural breast exam any longer, but they advised to “know your body” and know the alarm signals (retracting nipple etc), much the same way as you check for alterations in nevi. Most woman find small alterations anyway, said another, for instance when taking a shower. Indeed, exemplified by my own experience: 18 years ago my mother detected breast cancer when feeling a lump in her breast under the shower (malignant, but curable).
The Cochrane authors are also very clear in their review about the necessity of women noticing changes to their breast.

“Some women will continue with breast self-examination or will wish to be taught the technique. We suggest that the lack of supporting evidence from the two major studies should be discussed with these women to enable them to make an informed decision.
It would be wrong, however, to conclude that women need not be aware of any breast changes. It is possible that increased breast awareness may have contributed to the decrease in mortality from breast cancer that has been noted in some countries. Women should, therefore, be encouraged to seek medical advice if they detect any change in their breasts that may be breast cancer.”

Listen to this Podcast featuring the Cochrane authors to learn more about their findings

“Some women will continue with breast self-examination or will wish to be taught the technique. We suggest that the lack of supporting evidence from the two major studies should be discussed with these women to enable them to make an informed decision.
It would be wrong, however, to conclude that women need not be aware of any breast changes. It is possible that increased breast awareness may have contributed to the decrease in mortality from breast cancer that has been noted in some countries. Women should, therefore, be encouraged to seek medical advice if they detect any change in their breasts that may be breast cancer.”

Hier is de Podcast waarin de Cochrane auteurs over hun studie vertellen.

While I was on vacation Mariska Leeflang got her PhD. The ceremony was July 1st 2008.

Her thesis is entitled: Systematic Reviews of Diagnostic Test Accuracy.

Mariska is a colleague working (part time) at the Dutch Cochrane Centre(DCC). She studied veterinarian science in Utrecht, but gradually noticed that she was more interested in research than in veterinary practice. Four years ago she applied for a job at the dept. of Clinical Epidemiology, Biostatistics and Bioinformatics (KEBB) at the Amsterdam Academic Medical Centre (AMC). Having a cv with all kinds of odd subjects like livestock and courses delivering anesthetic drugs from a distance, she thought she would never make it, but she did.

Those 4 years have been very fruitful. She did research on diagnostic accuracy, is member of the Cochrane Diagnostic Test Accuracy Working Group and first author of one of the Cochrane pilot reviews of diagnostic test accuracy (chapter 7 of thesis). [Note: Cochrane Diagnostic Test Accuracy Reviews are a new initiative; till recently all Cochrane Systematic reviews were about health care interventions].Mariska also supports authors of Cochrane systematic reviews, gave many presentations and led many workshops. In fact, she also gave in-service training to our group of Clinical Librarians in diagnostic studies and together we have given several courses on Evidence Based Medicine and Systematic Reviews. In leisure time she is Chair of “Stichting DIO” (Vet Science & Development Cooperation)

Because of her backgound Mariska often gives her work a light “vet” touch.

“The cover of her thesis for instance is inspired by Celtic artwork and reflects the process of a systematic review: parts become a whole. The anthropomorphic (human-like) and zoomorphic (animal-like) creatures represent the background of the author. The stethoscopes and the corners refer specifically to diagnostic test accuracy reviews.The snakes eating their own tail stand in Celtic mythology for longevity and the ever-lasting life cycle.”

Also, she often closes her presentations with a slide showing swimming pigs, the pig being symbolic for “luck”.

So I would like to close this post in turn by wishing Mariska: “Good Luck”

The Cochrane Prognosis Methods group will be the 13th Cochrane Method Group. This group will have two primary roles: 1. Work with existing Cochrane entities, including Methods Groups to ensure the best use of prognostic evidence in Cochrane reviews 2. Conduct research to advance the methods of prognosis reviews and other types of reviews, where similar methods apply.

By calling into existence Method Groups like the Cochrane Prognosis, Cochrane Adverse Effects, Cochrane Screening and Diagnostic Tests and the Cochrane Qualitative Research Methods Group, the Cochrane Collaboration will no longer fully concentrate on Systematic Reviews of Randomized Controlled Trials / interventions. That has been a major criticism of the Cochrane Systematic Reviews.

For people not familiar with the structure of the Cochrane Collaboration, see the schematic picture below or follow this link

Abstract:
In part because of limited public access, Cochrane reviews are underused in the United States compared with other developed nations. To assess use of these reviews by opinion leaders, we examined citation of Cochrane reviews in the Clinical Expert Series of Obstetrics & Gynecology from inception through June of 2007. We reviewed all 54 articles for mention of Cochrane reviews, then searched for potentially relevant Cochrane reviews that the authors could have cited. Thirty-six of 54 Clinical Expert Series articles had one or more relevant Cochrane reviews published at least two calendar quarters before the Clinical Expert Series article. Of these 36 articles, 19 (53%) cited one or more Cochrane reviews. We identified 187 instances of relevant Cochrane reviews, of which 40 (21%) were cited in the Clinical Expert Series articles. No temporal trends were evident in citation of Cochrane reviews. Although about one half of Clinical Expert Series articles cited relevant Cochrane reviews, most eligible reviews were not referenced. Wider use of Cochrane reviews could strengthen the scientific basis of this popular series.

Despite their clinical usefulness, Cochrane systematic reviews of randomized controlled trials are underused in the United States. For example, a Cochrane review documenting that magnesium sulfate is ineffective as a tocolytic agent received little attention in the United States and Canada, where this treatment has dominated practice for several decades.[10] This therapy had been abandoned in other industrialized nations, where access to the Cochrane Library is easier.[11] Citizens of many countries have free online access to the Cochrane Library through governmental or other funding. In the United States, only Wyoming residents have public access through libraries, thanks to funding by its State Legislature.